The present invention relates to novel heterocyclic compounds derived from indole piperazines as well as their method of preparation, the pharmaceutical compositions containing them and their use as medicament.
Serotonin or 5-hydroxytryptamine (5-HT) plays an important role both at the level of the nervous system and at the cardiovascular level. Serotoninergic receptors have been identified both at the central and peripheral level. It is generally accepted that serotonin plays an important role in various types of pathological conditions such as
certain psychiatric disorders such as anxiety, depression, aggressiveness, panic attacks, obsessive-compulsive disorders, schizophrenia, suicidal tendency,
certain neurodegenerative disorders such as Alzheimer""s disease, Parkinsonism,
migraine, cephalagia, and
disorders linked to alcoholism
(cf. E. Zifa, G. Fillion, Pharm. Reviews, 44, 401, 1992; A. Moulignier, Rev. Neuro. (Paris) 150, 3-15, 1994; S. Langer, N. Brunello, G. Racagni, J. Mendlecvicz, xe2x80x9cSerotonin receptor subtypes: pharmacological significance and clinical implicationsxe2x80x9d Karger Ed.; (1992); B. E. Leonard, Int. Clin. Psychopharmacology, 7, 13-21 (1992); R. W. Fuller; J. Clin. Psychiatry, 53, 36-45 (1992); D. G. Grahame-Smith, Int. Clin, Psychopharmacology, 6. suppl. 4, 6-13, (1992).
The compounds according to the present invention are novel compounds having a very high affinity and a very good selectivity for the receptors commonly called 5-HT1-like and more particularly for the receptors called 5-HT1B and 5-HT1D.
The medicaments, alone or in combination with other therapeutic agents, including one or more active ingredients of the present invention find their use in the treatment, both curative and preventive, of diseases related to the dysfunction of the 5-HT1-like receptors including the 5-HT1B and 5-HT1D receptors, to their deregulation, or to modifications of the activity of the endogenous ligand which is generally serotonin.
The compounds of the present invention are potent agonists, both at the level of their affinity and at the level of their intrinsic efficacy or activity, and selective agonists for the 5-HT1B and 5-HT1D receptors. The agonists for the 5-HT1-like receptors, and more particularly for the 5-HT1B receptors, exhibit a selective vasoconstrictive activity and find their use in the treatment of migraine and of vasospastic disorders (A. Doenicke et al., The Lancet, 1, 1309-1311, 1988; M. D. Ferrari, P. R. Saxena, Cephalalgia, 13, 151-165, 1993; S. J. Peroutka, Headache, 30, 5-11, 1990; M. A. Moskowitz, TiPS, 13, 307-311, 1992; W. Feniuk, P. P. Humphrey, M. S. Perren, H. E. Connor, E. T. Whalley, J. Neurol. 238, pp. 57-61, 1991; A. V. Deligonis, S. J. Peroutka, Headache, 31, 228-231, 1991).
The compounds of the present invention, which are for the most part potent and selective agonists for the 5-HT1B and 5-HT1D receptors, therefore find their use more particularly in the curative and prophylactic treatment of attacks of conventional migraine, with aura, of common migraine, without aura, vascular facial pain, chronic vascular cephalalgia and vasospastic disorders.
The prior state of the art in this field is illustrated in particular by:
patent applications EP-A2-0303507, WO 93/14087, WO 94/02460, WO 92/14708, and patents U.S. Pat. No. 4,839,377, GB-A-2124210 and GB-A-2162532 which describe sulfonamides derived from typtamines, including sumatriptan, as antimigraine drugs,
patent applications GB-A-2191488, GB-A-2185020 and GB-A-2168347 which describe alkylamides derived from tryptamine.
French patent applications FR-A-2,699,918 and FR-A-2,707,639 which describe novel indole compounds derived respectively from piperazines and arylamines as ligands for the 5-HT1B and 5-HT1D receptors.
Application for patent of invention FR-A-2,724,933 which describes novel aromatic ethers derived from indole as ligands for the 5-HT1D receptors.
European patent applications EP-A-0313397, EP-A-0486666, EP-A1-0494774, EP-A-0494774, EP-A2-0497512, EP-A1-0501568, EP-A-0464558, EP-A1-0548813 and international applications WO 92/13856 and 93/11106 which describe heterocyclic derivatives derived from tryptamine as agonists for the 5-HT1-like receptors.
The present invention describes a novel class of piperazines derived from aminoindole which is distinguishable from all the closest prior art derivatives by their novel and different chemical structure, but also by their biological profile and their therapeutic potential since many compounds according to the present invention exhibit a very high affinity and selectivity for the 5-HT1B and 5-HT1D receptors, a remarkable efficacy and a particularly advantageous hemodynamic profile. The derivatives of the present invention therefore find their usefulness more particularly as active ingredients of medicinal compositions for the treatment of migraine and of various similar disorders.
The present invention relates to compounds of general formula (I). 
in which,
HET represents a heterocycle chosen from 
R1 and R2, which are identical or different, represent a hydrogen atom, Rxe2x80x21, CF3, CH2CF3, C6H5, CH2C6H5, OH, ORxe2x80x21, SH, SRxe2x80x21, Cl, F, Br, I, CN, NH2, NHRxe2x80x21, NRxe2x80x21Rxe2x80x22, NO2, NHxe2x80x94NH2, NHxe2x80x94NHRxe2x80x21, NHOH, NHCO2Rxe2x80x21, NHCONH2, NHCONRxe2x80x21Rxe2x80x22, NHSO2Rxe2x80x21, SO2Rxe2x80x21, SO2NH2, SO2NHRxe2x80x21, CORxe2x80x21, CO2Rxe2x80x21, CONH2, CONHRxe2x80x21, CONRxe2x80x21Rxe2x80x22 
which may be at the ortho or meta position on the aromatic ring,
R3 and R4, which are identical or different, represent a hydrogen atom, a linear or branched carbon-containing radical comprising from 1 to 6 carbon atoms or a benzyl or phenethyl residue,
Y and Z, which are identical or different, represent CH or N,
X represents O, S or NR7,
R5, R6 and R7, which are identical or different, represent a hydrogen atom, a linear or branched alkyl residue comprising from 1 to 6 carbon-atoms or a phenyl residue which is optionally substituted with a linear or branched alkyl residue comprising from 1 to 6 carbon atoms, a halogen atom, CF3, OCH3, CN or NO2,
Rxe2x80x21 and Rxe2x80x22, which are identical or different, represent a linear or branched alkyl group comprising from 1 to 6 carbon atoms or a phenyl residue which is optionally substituted with a linear or branched alkyl residue comprising from 1 to 6 carbon atoms, Cl, Br, F, I, OCH3, OH, NO2, SCH3,
as well as their salts, solvates and bioprecursors which are acceptable for therapeutic use.
The expression xe2x80x9cbioprecursorsxe2x80x9d as used in the present invention applies to compounds whose structure differs from that of the compounds of formula (I) but which, when administered to an animal or to a human being, are converted in the body to a compound of formula (I).
Among the compounds of general formula (I) which are included in the present invention, a class of compounds which is particularly appreciated corresponds to the compounds of general formula (I) in which R1, R2, R3 and R4 each represent a hydrogen atom.
Another class of compounds included in the present invention which is particularly appreciated corresponds to the compounds of general formula (I) in which HET represents a pyridyl or pyrimidyl residue.
A third class of compounds included in the present invention which is particularly appreciated corresponds to the compounds of general formula (I) in which HET represents a 5-membered heterocycle containing from 1 to 3 heteroatoms chosen from O, S or N.
Among the compounds of general formula (I) in the form of salts which are acceptable for therapeutic use, the salts formed by addition with inorganic acids, chosen from the hydrochlorides, hydrobromides, sulfates, fumarates, maleates, methanesulfonates and succinates, are preferred.
Other salts may be used in the preparation of the compounds of formula (I), for example the adducts with creatinine sulfate.
The present invention also relates to a method of preparing the compounds of general formula (I) which consists in the condensation of an aromatic piperazine of general formula (II) 
in which HET, R1 and R2 are defined as in general formula (I) with a carboxylic acid or a carboxylic acid derivative of general formula (III) 
in which Rxe2x80x23 and Rxe2x80x24 are identical respectively to R3 and R4 which are defined as in general formula (I), or Rxe2x80x23 or Rxe2x80x24 are precursors of or protecting groups for R3 and R4 which will be converted to R3 and R4 following the condensation of (II) with (III), and L represents OH, Cl, O-alkyl or the group xe2x80x94C(xe2x95x90O)L which represents the activated form of a carboxylic acid appropriate for the formation of an amide by reacting with an amine.
A particularly appreciated variant of the method of preparation of the invention uses an amine of formula (II) and a compound of formula (III) in which L represents Cl, in the presence of an organic or inorganic base such as pyridine, DMAP, DBU, K2CO3, Cs2CO3 or Na2CO3 in a polar aprotic anhydrous solvent such as THF, DME, dichloromethane, at a temperature of between xe2x88x9220xc2x0 C. and 40xc2x0 C.
A second particularly appreciated variant of the method of preparation of the invention uses the condensation of an amine of formula (II) with a compound of formula (III) in which L represents OH, in the presence of a tertiary amine such as triethylamine, diisopropylethylamine, pyridine, DMAP, N-methyl-morpholine, in a polar aprotic solvent such as THF, dichloromethane, DCE, ethyl acetate, chloroform, DMF, by reacting with an activating agent such as EDC, DCC, BOP, PyBOP, at a temperature of between xe2x88x9210 and 35xc2x0 C.
A method which is particularly appreciated in the context of this second variant consists in treating the compound of formula (III) in which L represents OH with ethyl chloroformate in the presence of a base such as, for example, a tertiary amine such as N-methylmorpholine, in a polar aprotic solvent such as dichloromethane, dichloroethane, THF and DME, at a temperature of between xe2x88x9220xc2x0 C. and 0xc2x0 C. followed by the addition of the amine of general formula (II).
In the specific case of the compounds of formula (I) in which R3 and R4 represent a hydrogen atom, the method of synthesis consists in condensing a heteroaromatic piperazine of general formula (II) with a carboxylic acid or a derivative of this carboxylic acid of general formula (III) in which Rxe2x80x23 represents a hydrogen atom and Rxe2x80x24 represents a protecting group t-butoxycarbonyl according to the methods and techniques previously described and then hydrolyzing the protecting group t-butoxycarbonyl in acidic medium, with the aid, for example, of hydrochloric acid or trifluoroacetic acid.
Another method of preparing the compounds of general formula (I) included in the present invention consists in converting an arylpiperazide derived from tryptamine of general formula (IV) 
in which R1 and R2, Rxe2x80x23 and Rxe2x80x24 are defined as above and P represents OSO2CF3, Br, I or CN to a compound of general formula (I) by various methods and techniques which will depend essentially on the nature of P in the precursor (IV) and on the nature of HET in the compound of general formula (I).
Accordingly, the compounds of general formula (IV) in which P represents I, Br or OSO2CF3 may be converted to compounds of general formula (I) by condensation with a boronic acid of formula HEP-B(OH) 2 in the presence of palladium according to the method well known to persons skilled in the art termed xe2x80x9cSuzuki couplingxe2x80x9d.
The compounds of general formula (IV) in which P represents CN are used as precursors of various compounds of general formula (I) as explained in the following scheme: 
It is clearly understood that, in the case where Rxe2x80x23 and Rxe2x80x24 are different from R3 and R4, the conversions indicated in this scheme imply the use of additional reactions to convert Rxe2x80x23, Rxe2x80x24 to R3, R4. Accordingly, the preparation of the compounds of general formula (I) in which R3 and R4 represent a hydrogen atom by the methods described in the above scheme use a precursor of general formula (IV) in which Rxe2x80x23xe2x95x90H and R4xe2x95x90COOtBu and an additional reaction intended to restore the primary amine such as the use of an acid such as hydrochloric acid or trifluoroacetic acid.
The aromatic piperazines of general formula (II) are prepared by various methods and techniques well known to persons skilled in the art for preparing arylpiperazines. In general, these intermediate piperazines are prepared from a precursor of general formula (V) 
in which HET, R1 and R2 are as described above, by reaction with an acid such as hydrochloric acid or preferably trifluoroacetic acid.
The intermediates of formula (V) are accessible from intermediates of general formula (VI) 
in which P is as described above.
The conversion of the arylpiperazines of formula (VI) to arylpiperazines of formula (V) is carried out by various methods and techniques described above for the conversion of the intermediates of general formula (IV) to compounds of formula (I).
In the specific case where, in general formula (V) at least one of the substituents R1 or R2 is an electron-attracting group, for example NO2, CF3, CN or CO2R, attached at the ortho position on the aromatic ring with respect to the piperazine residue, an alternative method for obtaining the arylpiperazines of formula (V) consists in condensing N-BOC-piperazine with an electophile of general formula (VII). 
in which HET and R2 are as defined above and R1 is an electron-attracting substituent, in the presence of an organic or inorganic base, at a temperature of between 20 and 100xc2x0 C.
The intermediates of general formula (II) may also be prepared from anilines of general formula (VIII) 
in which HET, R1 and R2 are defined as in general formula I, after reaction with electrophiles of formula (IX) or (X) 
in which Q represents a chlorine, a bromine, an iodine, a tosylate or a mesylate and Rx represents an amine-protecting group, for example a t-butoxycarbonyl, which will be subsequently deprotected. The condensation of anilines of general formula (VIII) with electrophiles of general formula (IX) is preferably carried out in a polar anhydrous solvent such as DMF, acetonitrile, THF, butanol, t-butanol or DMSO, generally at the reflux temperature of the solvent used, in the presence of an organic or inorganic base such as potassium, sodium or calcium carbonate.
The intermediates of general formula (II) may also be prepared by condensation of anilines of general formula (VIII) with derivatives of aminodiacids of formula (X), in the presence of acetic anhydride, followed by the reduction of the intermediate diketopiperazide thus formed with, for example, a borane and finally cleavage of the protecting group, for example in acidic medium if a t-butoxycarbonyl residue is involved.
The methods which make it possible to convert a derivative of formula (I) to another derivative of formula (I) in which at least one of the substituents HET, R1, R2, R3 or R4 is different, by techniques and methods well known to persons skilled in the art should also be considered as being included in the present invention.
Accordingly and by way of example, the derivatives of general formula (I) in which R1 represents an NO2 group may be converted to derivatives of formula (I) in which R1 represents NH2 by methods and techniques well known for this type of reduction as described for example in Comprehensive Organic Transformation, R. C. Larock, V. C. H., p. 412 1989, among which there may be mentioned atmospheric hydrogenation catalyzed by palladium-on-carbon, the use of SnCl2 or of zinc or alternatively rhodium catalyst in the presence of hydrazine. The compounds of formula (I) in which R1 represents NH2 may also be converted to derivatives of formula (I) in which R1 represents NR8R9, NHCO2R8, NHCOR8R9, NHSO2R8, by methods and techniques well known to persons skilled in the art for converting an aromatic amine to amide, carbamate, urea or sulfonamide.
In the context of this invention, it is also necessary to consider the preparation of compounds of formula (I) from other compounds of formula (I) which are distinguishable by the nature of the HET-residue. Accordingly, the derivatives of general formula (I) in which HET represents a tetrazole residue may be converted to derivatives of formula (I) in which HET represents an oxadiazole according to-the scheme below: 
It is evident that in some chemical reactions or reaction sequences which lead to the preparation of compounds of general formula (I), it is necessary or desirable to protect possible sensitive groups in the side reactions. This may be achieved by the use, i.e. the introduction and the deprotection, of conventional protecting groups such as those described in xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, T. W. Greene, John Wiley and Sons, 1981, and xe2x80x9cProtecting Groupsxe2x80x9d, P. J. Kocienski. Thieme Verlag, 1994. The appropriate protecting groups will therefore be introduced and removed during the step most appropriate for doing this, using the methods and techniques described in the references cited above.
When it is desired to isolate a compound according to the invention in the form of a salt, for example an addition salt with an acid, this can be achieved by treating the free base of general formula (I) with an appropriate acid, preferably in an equivalent quantity.
The present invention also relates to the compounds of formula (I) for their application as therapeutically active substances.
The present invention relates more particularly to the compounds of formula (I) for the treatment or prevention of serotonin-related disorders, for the treatment or prevention of migraine, vascular facial pain, chronic vascular cephalalgia, for the treatment or prevention of depression, obsessive-compulsive disorders, bulimia, aggressiveness, alcoholism, nausea, sexual dysfunction, antisocial behavior, anxiety, spasticity, Alzheimer""s and Parkinson""s diseases.
The present invention also relates to the pharmaceutical compositions containing, as active ingredient, at least one compound of formula (I) and a pharmaceutically acceptable excipient.
The compositions according to the invention may be used by the oral, nasal, parenteral, rectal or topical route.
As solid compositions for oral administration, there may be used tablets, pills, powders in the form of gelatin capsules or cachets, granules. In these compositions, the active ingredient according to the invention is mixed with one or more inert diluents such as starch, cellulose, sucrose, lactose or silica, under an argon stream. These compositions may also comprise substances other than the diluents, for example one or more lubricants such as magnesium stearate or talc, a coloring, a coating or a glaze.
As liquid compositions for oral administration, there may be used pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or paraffin oil. These compositions may comprise substances other than the diluents, for example wetting, sweetening, thickening, flavoring or stabilizing products.
The sterile compositions for parenteral administration may be preferably solutions which are aqueous or non-aqueous, suspensions or emulsions. As solvent or vehicle, it is possible to use water, propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate or other suitable organic solvents. These compositions may also contain adjuvants, in particular wetting, isotonizing, emulsifying, dispersing and stabilizing agents. The sterilization may be performed in several ways, for example by asepticizing filtration, by incorporating sterilizing agents into the composition, by irradiation or by heating. They may also be prepared in the form of sterile solid compositions which may be dissolved at the time of use in sterile water or any other injectable sterile medium.
The compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active product, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.
The compositions for topical administration may be, for example, creams, lotions, collyria, collutoria, nasal drops or aerosols.
The doses depend on the desired effect, the duration of the treatment and the route of administration used; they are generally between 0.001 g and 1 g, preferably between 0.005 g and 0.25 g per day, preferably by the oral route for an adult with unit doses ranging from 0.1 mg to 500 mg of active substance, preferably from 1 mg to 50 mg.
In general, the doctor will determine the appropriate dosage according to the age, weight and all the other factors specific to the subject to be treated.
The following examples illustrate the-invention without, however, limiting the scope thereof.